The entry of HIV-1 into target cells requires interactions between the viral envelope (Env) protein, CD4, and a chemokine receptor coreceptor. Attachment of virus to the cell surface, which may be the rate limiting step to infection, can be mediated by interactions with a variety of molecules, only some of which have been well characterized. Gp-340 is a member of the scavenger receptor cysteine-rich family. It is found on alveolar macrophages and binds surfactant proteins to clear bacteria as part of the lung innate immune system. We previously demonstrated that gp-340 binds HIV Env with high affinity and, in its soluble form, inhibits HIV infection. Certain specific antibodies against gp-340 inhibit binding of Env to gp-340 and treatment of monocyte derived macrophages expressing cell surface gp-340 with such antibodies diminishes acute HIV-1 infection; suggesting that soluble and cell surface gp-340 have opposite effects on viral infection. Gp-340 is also expressed by epithelial cells including ones that line the genital tract. We observed that pulsing of genital epithelial cells expressing gp-340 with HIV results in efficient binding and transfer of infection to CD4+ T cells trans-infection). The binding by gp-340 increases the infectivity and half-life of virus and can be inhibited by anti-gp-340 antibodies and Env peptides shown to bind to gp-340. Unlike other HIV Env binding molecules that do not mediate fusion but promote trans-infection (DC-SIGN, syndecan, and mannose receptor) that bind Env carbohydrate, the interaction between gp-340 and Env appears to involve protein on Env. The hypothesis is that through specific interactions between gp-340 and HIV Env; gp-340 mediates trans- HIV infection. We will test this hypothesis in four specific aims: 1) the Identification of the epitope and amino acid residues of gp-340-Tm used in binding to HIV Env; 2) the analysis of Env determinants important in binding to gp-340-Tm; 3) the investigation of the role of gp-340-Tm in transmission of HIV; and 4) studies of the trafficking of HIV after binding to genital tract epithelial cells expressing endogenous gp-340. As gp-340 is expressed in many areas of HIV immunopathogenesis (lung, brain, lymphoid tissue) and transmission (genital epithelial cells), these studies will be important in further understanding HIV transmission and pathogenesis and for formulating potential avenues of interference in HIV transmission, infection, and replication.